LJUBLJANA, SLOVENIA – Passive protection of infants from severe respiratory syncytial virus lower respiratory tract infection during the first 6 months of life has convincingly been achieved through maternal immunization using a novel nanoparticle vaccine in the landmark PREPARE trial.
“I think it’s important for everyone, especially people like myself who’ve been working on maternal immunization for about 20 years, to realize that this is a historic study,”, declared in reporting the study results at the annual meeting of the European Society for Paediatric Infectious Diseases.
“We have here for the first time a phase-3, global, randomized, placebo-controlled, observer-blinded clinical trial looking at an experimental vaccine in pregnant women for the protection of infants from a disease for which we really don’t have other potential solutions quite yet, and in a period of high vulnerability,” said Dr. Munoz, a pediatric infectious disease specialist at Baylor College of Medicine, Houston.
Indeed, respiratory syncytial virus (RSV) is the No. 2 cause of mortality worldwide during the first year of life. Moreover, most cases of severe RSV lower respiratory tract infection occur in otherwise healthy infants aged less than 5 months, when active immunization presents daunting challenges.
“While certainly mortality is uncommon in high-income countries, we do see significant hospitalization there due to severe RSV lower respiratory tract infection in the first year of life, sometimes more than other common diseases, like influenza,” she noted.
PREPARE included 4,636 women with low-risk pregnancies who were randomized 2:1 to a single intramuscular injection of the investigational RSV vaccine or placebo during gestational weeks 28-36, with efficacy assessed through the first 180 days of life. The study took place at 87 sites in 11 countries during 4 years worth of RSV seasons. Roughly half of participants were South African, one-quarter were in the United States, and the rest were drawn from nine other low-, middle-, or high-income countries in the Northern and Southern Hemispheres. The median gestational age at vaccination was 32 weeks.
The primary efficacy endpoint specified by the Food and Drug Administration – but not other regulatory agencies – was the placebo-subtracted rate of RSV lower respiratory tract infection as defined by RSV detected by reverse transcription polymerase chain reaction, along with at least one clinical manifestation of lower respiratory tract infection, oxygen saturation below 95%, and/or tachypnea. The risk of this outcome was reduced by 39% during the first 90 days of life and by 27% through 180 days in infants in the maternal immunization group, a difference which didn’t achieve statistical significance.
However, prespecified major secondary endpoints arguably of greater clinical relevance were consistently positive. Notably,when levels of transplacentally transferred neutralizing antibodies against RSV A and B were highest, with events occurring in 57 of 2,765 evaluable infants in the active treatment arm and in 53 of 1,430 controls. Similarly, there was a 40% reduction through day 180. Moreover, rates of another key secondary endpoint – RSV lower respiratory tract infection plus severe hypoxemia with an oxygen saturation below 92% – were reduced by 48% and 42% through days 90 and 180, respectively. Thus, the vaccine’s protective effect was greatest against the most severe outcomes of RSV infection in infancy, according to Dr. Munoz.
No safety signals related to this immunization strategy were seen during 1 year of follow-up of infants and 6 months for the mothers. Side effects were essentially limited to mild, self-limited injection site reactions, with zero impact on pregnancy and delivery.
An intriguing finding in an exploratory analysis was that the vaccine appeared to have ancillary benefits beyond prevention of medically significant RSV disease in the young infants. For example, the rate of all lower respiratory tract infections with severe hypoxemia – with no requirement for demonstration of RSV infection – was reduced by 46% during the first 90 days of life in the immunized group. Similarly, the rate of all-cause lower respiratory tract infection resulting in hospitalization was reduced by 28%.
“This is actually quite interesting, because these are unexpected benefits in terms of all-cause effects,” the pediatrician commented, adding that she and her coinvestigators are delving into this phenomenon in order to gain better understanding.
Additional analyses of the recently completed PREPARE study are ongoing but already have yielded some important findings. For example, women immunized before 33 weeks’ gestation had significantly greater transplacental antibody transfer than those immunized later in pregnancy, with resultant markedly greater vaccine efficacy in their offspring as well: A placebo-subtracted 70% reduction in RSV lower respiratory tract infection with severe hypoxemia through 90 days, compared with a 44% reduction associated with immunization at gestational week 33 or later. And when the interval between immunization and delivery was at least 30 days, the risk of this endpoint was reduced by 65%; in contrast, there was no significant difference between vaccine and placebo groups when time from immunization to delivery was less than 30 days.
Also noteworthy was that maternal immunization afforded no infant protection in the United States. This unanticipated finding is still under investigation, although suspicion centers around the fact that RSV seasons were generally milder there, and American women were vaccinated at a later gestational age, with a corresponding shorter interval to delivery.
The novel recombinant nanoparticle vaccine tested in PREPARE contains a nearly full-length RSV fusion protein produced in insect cells. The nanoparticles express both prefusion epitopes and epitopes common to pre- and postfusion conformations. Aluminum phosphate is employed as the adjuvant.
Novavax’s stock price has been kicked to the curb since the company earlier reported that a large phase 3 trial of the vaccine failed to meet its primary endpoint for prevention of RSV lower respiratory tract infection in older adults. Now the vaccine’s failure to meet its prespecified FDA-mandated primary endpoint in the maternal immunization study will doubtless spawn further financially dismissive headlines in the business press as well.
But pediatricians are famously advocates for children, and PREPARE received a warm welcome from the pediatric infectious disease community, regardless of investor response. Indeed, PREPARE was the only clinical trial deemed of sufficient import to be featured in the opening plenary session of ESPID 2019.
Ulrich Heininger, MD, professor of pediatrics at the University of Basel (Switzerland), who cochaired the session, jointly sponsored by ESPID and the Pediatric Infectious Diseases Society, declared, “These findings, I think, are a great step forward.”
Dr. Munoz reported receiving research grants from Janssen, the National Institutes of Health, the Centers for Disease Control and Prevention, and Novavax, which sponsored the PREPARE trial, assisted by an $89 million grant from the Bill and Melinda Gates Foundation.